Existing Immunotherapy Techniques
The rise in prevalence of allergic diseases is part of the new epidemic of non-communicable diseases associated with urbanization and progress, adoption of western lifestyles in developing countries, and exposure to various chemicals that are commonly used in current urban and developed environments. This rise in prevalence is associated with disruptions in the biome, excessive hygiene, and lack of exposure to natural environments such as barns, farms, and soil. Allergic diseases are thought to affect 20% to 30% of the population, but current numbers attest to an increase in the recent past. The cost of these diseases to society, healthcare systems, and affected individuals and their families is substantial.
The pharmacological treatment of allergic diseases includes use of over-the-counter antihistamines, decongestants, and intranasal steroids, prescription nasal steroids, and leukotriene receptor blockers. Domestic environmental intervention is designed to minimize exposure to indoor allergens, and when this fails or is insufficient, immunotherapy becomes the logical clinical step to follow.
The most widely used method of immunotherapy for the treatment of allergic disease is subcutaneous immunotherapy (“SCIT”), which utilizes allergen injections. This treatment method is invasive, painful, and time-consuming. Moreover, methods for subcutaneous immunotherapy administration have changed little since 1911. Injection-based methods typically consist of a buildup phase comprising about 100 to 400 separate injections over a period of 20 weeks (under ideal conditions with no interruptions or adverse reactions). Injection-based immunotherapy methods bear undesirable risks of adverse reactions that can be localized, generalized, near-fatal, or even fatal. In this context, improved methods of immunotherapy for treating allergic disease that are more amenable to modern lifestyles and carry much less risk to patients are needed.
Sublingual immunotherapy (“SLIT”) is a somewhat newer treatment modality used to treat allergic disease. SLIT involves sublingual administration of a custom-formulated allergy serum over an extended period of time to gradually create immunity to a patient's specific allergic triggers. This form of immunotherapy is much less invasive than allergy shots and requires less nursing staff and office visits, as the majority of the treatment is self-administered by patients at home. Unfortunately, however, SCIT remains the preferred treatment by health insurance companies in the United States.
Circadian Rhythms and Components of the Immune System
Circadian rhythms recur in physiological, biochemical, metabolic, behavioral, and other parameters. Circadian rhythms cycle approximately every 24 hours and persist in the absence of external time cues. These internally-generated rhythms are the product of a complex circadian timing system with a master pacemaker located in the suprachiasmatic nuclei of the anterior hypothalamus, synchronizing semi-automatic circadian pacemakers throughout the central nervous system and the periphery in order to impose a daily temporal architecture on mammalian physiology and behavior. This system allows physiological and cellular functions to be coordinated in time for both energy conservation processing and for the time segregation of opposing processes.
Circadian rhythmicity also affects the function of the immune system with variations of immunocompetent cells and cytokines and assuring a well-timed anticipatory organization of biological processes that play a critical role in the preservation of homeostasis and defense. At the intracellular end, circadian clocks are regulated by a set of clock genes activated by transcription factors CLOCK and BAML1.
For example, T and B lymphocyte concentrations are considerably higher at night. CD4+ (T helper) and CD8+ (cytotoxic)-naïve, central memory, and effector memory T lymphocytes show peak numbers at night, whereas CD4+ effector T cells show no rhythm and CD8+ effector T cells show a low-amplitude rhythm with peaks during the day. Granulocytes, monocytes, and natural killer cells have shown their numbers to peak midday or late in the day. Serum levels and in vitro production of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-γ), and IL-1, IL-2, IL-6, and IL-12 peak at night or early in the morning.
Antigen presenting cells (APCs) are involved in the capture and processing of allergens and the subsequent presentation of pathogen-derived peptides to native T cells in the lymph nodes, tonsils, and adenoids. APCs are located in the superficial layers of the oral mucosa and consist of CD 207+ Langerhans cells and CD 11b+, CD 68+, and CD206+ macrophages located in the lamina propria. APCs capture allergens by phagocytosis and by IgE mediation, as they are FcεR1 positive. APCs exhibit a tolerogenic phenotype in that they produce IL-10 and TGF 13, and they express indoleamine 2,3-dioxygenase. Macrophages secrete IL-10 and IL-12 and express retinaldehyde dehydrogenase 2 as a consequence in the absence of danger signals. The default response of oral APCs to allergens is intolerance as opposed to inflammation within the induction of IFN-γ producing and IL-10 secreting TH-1 and regulatory T cells (Tregs), respectively, in draining cervical lymph nodes.
Sleep supports the immunological synapse between APC and the T cells in lymph nodes. During sleep, there is increased production of pro-inflammatory Th1-supporting hormones such as melatonin, GH, prolactin, and leptin, whereas anti-inflammatory hormones such as cortisol and catecholamine reach a nadir. This pro-inflammatory hormonal boost during sleep acts like an adjuvant, presumably on APCs, which show a sleep-dependent production of IL-12, which in turn supports Th1 lineage commitment (Dimitrov et al., 2007; Lange et al., 2006, 2011). The regulatory role of APCs mediating the sleep-associated peak of T cell cytokine production is substantiated by the fact that the rhythm in cytokine production of isolated CD4+ T cells is shifted by several hours (Bollinger et al., 2011).
In contrast, the initiation of a Th1 immune response that evolves more slowly requiring the interaction between APC and T cell in lymph nodes, protein biosynthesis, and cell proliferation is supported during sleep. The Th1 response is energy consuming and involves the release of pro-inflammatory mediators associated with pain, immobility, and malaise; therefore, its timing to the sleep period seems reasonable. B and T cells harbor an intrinsic clock, but additional regulatory influences of sleep, locomotor activity, hormonal changes, and APC activity entrain the rhythm of lymphocyte numbers and functions. In many, but not all in vivo studies, adaptive immune responses such as the delayed-type hypersensitivity reaction, as well as the T cell and antibody response to immunizations, benefit from sleep. Such a time-limited boost of lymphocyte activity may serve immune homeostasis and maximize efficiency of the immune system.
Oral Immunological Milieu
The oral cavity contains an abundance of immunologically-active tissues (tonsils, adenoids, and lymph nodes). This expedites the process of efficient antigen presentation. The low concentration of mast cells guarantees safe allergen administration via vestibular immunotherapy. According to Allam (Allergy 2008), there is a substantial concentration of dendritic cells in the oral vestibular space.
There is no current literature, guidelines, or recommendations regarding the management in patients who do not tolerate or have failed to respond to SCIT. Commonly, treatment is interrupted and patients continue to experience symptoms managed only with pharmacotherapy. Thus, there remains a need in the art for improved compositions and methods for treating allergic disease. The embodiments disclosed herein are aimed at overcoming these and other needs in the art.